Autoubiquitination

Autoubiquitination is the process by which a ubiquitin ligase (an E3 enzyme) attaches ubiquitin molecules to itself. This self-modification can regulate the ligase’s stability, activity, interactions, and subcellular localization, thereby influencing cellular signaling and protein turnover. Autoubiquitination occurs within the ubiquitin–proteasome system, following the general cascade in which ubiquitin is activated by E1, transferred to an E2, and then conjugated to a substrate by an E3 ligase; in autoubiquitination, the substrate is the E3 ligase itself.

The fate of autoubiquitination depends on the type of ubiquitin linkage. K48-linked chains commonly target the ligase for proteasomal degradation, reducing its cellular abundance. K63-linked chains, and monoubiquitination, often regulate the ligase’s activity, interactions, or localization without necessarily triggering degradation. Different E3 ligases use distinct mechanisms: RING-type ligases typically recruit substrates for direct ubiquitination, while HECT- and RBR-type ligases form a thioester intermediate with ubiquitin, allowing controlled autoubiquitination.

Autoubiquitination is reversible by deubiquitinases, which can remove ubiquitin chains and restore ligase function. It serves as a regulatory mechanism to prevent excessive ligase activity, to modulate signaling responses, or to promote turnover of the ligase in response to cellular cues. An example is MDM2, a negative regulator of p53, which can undergo autoubiquitination leading to its degradation.

Autoubiquitination thus represents a key layer of control within the ubiquitin system, balancing protein turnover with dynamic signaling needs.